TOXICOLOGY

TOXICOLOGY

• Deal with adverse or undesired

effects of drugs.

• Initial toxicology studies are

conducted on rodents.

• Another animal: Dog is added.

The toxicology profile

• Acute or short-term toxicity.

• subacute.

• subchronic toxicity.

• chronic toxicity.

• carcinogenicity testing.

• reproduction studies.

• mutagenicity screening.

Acute or Short-Term Toxicity Studies

• Designed to determine the toxic

effects of a test compound when

administered in a single dose

and/or in multiple doses over a

short period, usually a single

day.

• Animals compared with controls for eating and drinking habits, weight change, toxic effects, psychomotor changes, and any other signs over 30 day post dose period.

• Feces and urine specimens are collected and clinical laboratory tests performed to detect changes in clinical chemistry and other changes that could indicate toxicity.

• unwanted effects, for 30-day post dose period. Feces and urine specimens collected and laboratory tests performed to detect changes

• Animal deaths are recorded

Subacute or Subchronic Studies

• Animal toxicity studies of 3 doses daily

for 2 weeks to 2 animal species are

required.

• The initial human dose is 1/10 of highest

nontoxic dose (in mg/ kg of subject's weight)

shown during animal studies.

Chronic testing

• Drugs given to humans for week

or more, animal studies of 90 to

180 days.

• animal studies for 1 year. Some animal

toxicity studies last 2 years or longer.

Carcinogenicity Studies

• Carried out in limited number of rat and

mouse strains when there is information on

spontaneous tumor incidence.

• done with female and male animals using

high, intermediate, and low doses over a 90

day.

• Carcinogenicity studies are long term (18

to 24 months), with surviving animals

killed and studied at defined weeks

during the test period.

• animal death (other than killing).

• tumor incidence

• Any preneoplastic lesions

Reproduction Studies

• Any effect of drug on mammalian reproduction.

• Embryonic, prenatal, and postnatal

development.

• Multigenerational effects; and teratology.

• Reproductive studies, on rat.

• In embryo toxicity rabbit is studied in addition to

rat.

Genotoxicity or Mutagenicity

Studies

• performed to determine effect on gene,

mutation or cause chromosome or

DNA damage.

• Strains of Salmonella typhimurium are

routinely used in assays to detect

mutations.

Preformulation studies

•solubility, partition

coefficient, dissolution

rate, physical form, and

stability.

Drug Solubility

• A drug administered by any route must

possess aqueous solubility for systemic

absorption and therapeutic response.

• Poorly soluble compounds have

incomplete, absorption thus produce

minimal response.

• Increase aqueous solubility by:

1. prepare more soluble derivatives of

parent compound, such as salts or esters,

by chemical complexation,

2. by reducing particle size.

Partition Coefficient

• To produce a pharmacologic response, a drug

molecule must cross biologic membrane of protein

and lipid, which acts as lipophilic barrier to many

drugs.

• The ability of a drug to penetrate this barrier based

on lipids solubility(lipophilic) versus aqueous

phase (hydrophilic). Partition coefficient is

measure of distribution in lipophilic-hydrophilic

phase system and indicates its ability to penetrate

biologic multiphase systems.

Dissolution Rate • The speed a drug substance dissolves in

medium called its dissolution rate.

• dissolution constant, and partition coefficient,

can provide indication of drug's absorption

potential.

• For a chemical entity, its acid, base, or salt

forms, as well as its physical form (e.g.,

particle size), may result in differences in

dissolution rate.

Physical Form

• The crystal or amorphous forms and/or the

particle size of a powdered drug can affect the

dissolution rate, thus the rate and extent of

absorption, for a number of drugs.

• Reducing particle size increase surface area

of poorly soluble drug its dissolution rate in

the gut is enhanced.

Stability • Chemical and physical stability of drug

alone, and when combined with formulation

components, is critical to preparing a

successful pharmaceutical product.

• For drugs susceptible to oxidative

decomposition, the addition of antioxidant

stabilizing agents to the formulation may be

required to protect the potency.

• Drugs destroyed by hydrolysis, protection against moisture in formulation, processing, and packaging may be required to prevent decomposition.

• In every case, drug stability testing at various temperatures, conditions of relative humidity (RH)—as 40°C 75% RH/30°C 60% RH—durations, and environments of light, air, and packaging is essential in assessing drug and drug product stability. Such information is vital in developing label instructions for use and storage, assigning product expiration dating, and packaging and shipping.

• During Phase 1 studies: oral drugs capsules

are employed containing active ingredient

alone.

• Excipients included in the formulation for

Phase 2 trials.

• studies drug's ADME undertaken

• During Phase 2, the final dosage form is

selected and developed for Phase 3 trials; this

is the formulation that is submitted to the FDA

for marketing approval.

Drug effect in a population sample.

• Certain drugs may produce more than one effect, depending on dose. For example, a low dose of barbiturate produces sedation, whereas a larger dose produces hypnotic effects.

• Age: newborns and those born prematurely, have immature hepatic and renal function, the means by which drugs are normally inactivated and eliminated from the body.

• Age or weight is not enough in determine

pediatric dose.

• Many pediatric doses based on body weight or

body surface area (BSA).

• Elderly persons: physiologic functions decrease

after 30 years. cardiac output decrease 1%/year from

age 20 to 80.

• GFR falls progressively until age 80; at time it is

only half of what it was at age 20.

• Vital capacity, immune capacity, and liver enzyme

function also decrease. The decrease in renal and

hepatic function in elderly slows drug clearance rate

.

Accumulation and toxicity • Chronic disorders in old patients require

concomitant drug therapy, increasing

1. drug-drug interactions and

2. adverse effects.

• Pharmacogenetics varying effects among

different racial populations.

• Common genetic polymorphisms: multiple

forms of enzymes governing drug metabolism,

affect clearance from blood of many drugs used

in large patient populations

Body Weight • Usual doses for drugs are suitable for 70-kg (150 lb)

individuals.

• The ratio between amount of drug administered and the

size of the body influences drug concentration in body

fluids. Therefore, drug dosage require adjustment heavy

patients.

• Mg (drug) /kg (body weight) basis (e.g., 1 mg/kg).

• Body weight is more dependable than age

• In some instances, pediatric dose based on a

combination age and weight (e.g., 6 months to 2 years of

age: 3 mg/kg/day).

Body Surface Area • Some drug doses based on (e.g., 1 mg/M2

BSA).

• The BSA for child or adult determined

using nomogram.

• The BSA determined at intersept of a

straight line drawn to connect an

individual's height and weight.

• For example, an adult measuring 67 in. in

height and weighing 132 lb would have a

BSA of approximately 1.7 m2.

Sex • Pharmacokinetic differences between women and

men. important for narrow therapeutic index.

• Drugs with narrow therapeutic risk increase to toxic

levels or decrease to ineffective levels with minimal

dosing changes.

• great caution is advised for use of most drugs during

pregnancy and in women of childbearing age. Similar

caution is applicable to drug use in nursing mothers

because transfer from mother's milk to an infant is

well documented for a variety of drugs.

Pathologic State • example, if drugs used in presence of renal

impairment, excessive systemic accumulation

occur, risking toxicity.

• In such conditions, lower doses are indicated, and if

therapy is prolonged, blood levels should be

assessed and the patient monitored at regular

intervals to ensure the maintenance of nontoxic

levels of the drug.

Tolerance

• Tolerance common with antihistamines

and narcotic analgesics.

• After tolerance, normal response may be

regained by suspending the drug's

administration for a while.

Concomitant Drug Therapy • Absorption rapid if stomach and upper

part of intestine are empty.

• A dose of drug that is effective when

taken before a meal less effective if

administered during or after eating.

• Drug-food interactions can affect a drug's

absorption.

Dosage Form and Route of Administration

• Varying rates and degrees of absorption occur from drug administration in rectum, GIT, under tongue, via skin, and to other sites.

• Therefore, for a given drug, different dosage forms and routes of administration are considered new by the FDA.

DRUG PRODUCT LABELING

• Drug labeling includes not only the labels placed on an immediate container but also the information on

1. the packaging,

2. in package inserts, and

3. in company literature,

4. advertising, and promotional materials.

Label contain:

• Description of the product • Clinical pharmacology • Indications and usage • Contraindications • Warnings • Precautions: • Adverse reactions • Drug abuse and dependence • Overdosage, including signs, symptoms • Dosage and administration • How supplied

• FDA REVIEW AND ACTION LETTERS

• POSTMARKETING REPORTING OF

ADVERSE DRUG EXPERIENCE

• Annual reports

• Failure to make required reports may lead to FDA withdrawal of approval for marketing.

SUPPLEMENTAL NEW DRUG APPLICATION

• A change in the method of synthesis

• Change in the formulation

• Use of a different facility or contractor to manufacture

• Change in the container and closure system

• Extension of the expiration date

• Any labeling change

• Animal drug applications

• It allows veterinarians to prescribe extra label uses of approved animal drugs and approved human drugs for animals.

• • Medical devices

• FDA has regulatory authority over the manufacture and licensing of all medical devices, from surgical gloves and catheters to cardiac pacemakers and cardiopulmonary bypass blood gas monitors.

Stability testing of new drug substances and products

• Validation of analytical procedures .

• Impurities in new drug substances

• Impurities in new drug products

• Nonclinical safety studies for the conduct of human clinical

trials for pharmaceuticals

• Preclinical testing of biotechnology-derived pharmaceuticals

• General considerations for clinical trials

• Studies in support of special populations: geriatrics

• Ethnic factors in the acceptability of foreign data

• Repeated dose-tissue distribution studies

• Dose selection for carcinogenicity studies of pharmaceuticals

• Dose-response information to support drug registration